title: New aspects on efficient anticoagulation and antiplatelet strategies in sheep.
abstract: BACKGROUND
  After addressing fundamental questions in preclinical models in vitro or in small animals in vivo, the translation into large animal models has become a prerequisite before transferring new findings to human medicine. Especially in cardiovascular, orthopaedic and reconstructive surgery, the sheep is an important in vivo model for testing innovative therapies or medical devices prior to clinical application. For a wide variety of sheep model based research projects, an optimal anticoagulation and antiplatelet therapy is mandatory. However, no standardised scheme for this model has been developed so far. Thus the efficacy of antiplatelet (acetylsalicylic acid, clopidogrel, ticagrelor) and anticoagulant (sodium enoxaparin, dabigatran etexilate) strategies was evaluated through aggregometry, anti-factor Xa activity and plasma thrombin inhibitor levels in sheep of different ages.
  
  
  RESULTS
  Responses to antiplatelet and anticoagulant drugs in different concentrations were studied in the sheep. First, a baseline for the measurement of platelet aggregation was assessed in 20 sheep. The effectiveness of 225 mg clopidogrel twice daily (bid) in 2/5 sheep and 150 mg bid in 3/5 lambs could be demonstrated, while clopidogrel and its metabolite carboxylic acid were detected in every plasma sample. High dose ticagrelor (375 mg bid) resulted in sufficient inhibition of platelet aggregation in 1/5 sheep, while acetylsalicylic acid did not show any antiplatelet effect. Therapeutic anti-factor Xa levels were achieved with age-dependent dosages of sodium enoxaparin (sheep 3 mg/kg bid, lambs 5 mg/kg bid). Administration of dabigatran etexilate resulted in plasma concentrations similar to human ranges in 2/5 sheep, despite receiving quadruple dosages (600 mg bid).
  
  
  CONCLUSIONS
  High dosages of clopidogrel inhibited platelet aggregation merely in a low number of sheep despite sufficient absorption. Ticagrelor and acetylsalicylic acid cannot be recommended for platelet inhibition in sheep. Efficient anticoagulation can be ensured using sodium enoxaparin rather than dabigatran etexilate in age-dependent dosages. The findings of this study significantly contribute to the improvement of a safe and reliable prophylaxis for thromboembolic events in sheep. Applying these results in future translational experimental studies may help to avoid early dropouts due to thromboembolic events and associated unnecessary high animal numbers.
authors.affiliation: Department of Plastic and Hand Surgery, University Hospital of Erlangen Friedrich-Alexander University of Erlangen-Nürnberg, Krankenhausstr, 12, Erlangen D-91054, Germany. justus.beier@uk-erlangen.de.
authors.forename: Annika
authors.initials: A
authors.lastname: Weigand
authors.forename: Anja M
authors.initials: AM
authors.lastname: Boos
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ringwald
authors.forename: Maren
authors.initials: M
authors.lastname: Mieth
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kneser
authors.forename: Andreas
authors.initials: A
authors.lastname: Arkudas
authors.forename: Oliver
authors.initials: O
authors.lastname: Bleiziffer
authors.forename: Dorothee
authors.initials: D
authors.lastname: Klumpp
authors.forename: Raymund E
authors.initials: RE
authors.lastname: Horch
authors.forename: Justus P
authors.initials: JP
authors.lastname: Beier
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012756:Sheep; D012757:Sheep Diseases / Q000517:prevention & control*; D013927:Thrombosis / Q000517:prevention & control / Q000662:veterinary*
chemical_list: D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors